Glucokinase (GK) is one of four hexokinases found in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 19733]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic xcex2-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin S. R., Kelly, K. L., and Ruderman, N. B. in Joslin""s Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations ( less than 1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Oranner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in xcex2-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in xcex2-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in xcex2-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents are useful for treating type II diabetes.
This invention provides a tetrazole selected from the group consisting of a compound of the formula: 
where one of R1 or R2 is 
(this tetrazole is linked to the remainder of the molecule by the N, as represented here) and the other is hydrogen, halogen, lower alkyl sulfonyl, perfluoro-lower alkyl, cyano, or nitro; R3 is cycloalkyl; R4 is xe2x80x94C(O)xe2x80x94NHR6 or a five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group shown, which heteroaromatic ring contains from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen with a first heteroatom being nitrogen adjacent to the connecting ring carbon atom, said heteroaromatic ring being unsubstituted or monosubstituted with halogen at a position on a ring carbon atom other than that adjacent to said connecting carbon atom; n is 0 or 1; R5 is lower alkyl, or perfluoro lower alkyl; R6 is hydrogen or lower alkyl; and pharmaceutically acceptable salts of the tetrazole.
Formula I-A depicts the isomeric bond when it is not hydrogenated. Formula I-B depicts the bond when it is hydrogenated. Accordingly the xcex94 denotes a trans configuration across the double bond in formula I-A, and the * represents the asymmetric carbon atom in formula I-B. Tetrazoles which are compounds of formula I-B are preferably in the R configuration.
The compounds of formula IA or IB are glucokinase activators useful for increasing insulin secretion in the treatment of type II diabetes.
One embodiment of formula I-A or of formula I-B is a tetrazole where R4 is a five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group shown, which heteroaromatic ring contains from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen with a first heteroatom being nitrogen adjacent to the connecting ring carbon atom, said heteroaromatic ring being unsubstituted or monosubstituted with halogen at a position on a ring carbon atom other than that adjacent to said connecting carbon atom. Formula I-A1 represents this embodiment as a compound of formula I-A, and Formula I-B1 represents this embodiment as a compound of formula I-B.
Another embodiment of formula I-A or formula I-B is a tetrazole where R4 is xe2x80x94C(O)xe2x80x94NHR6 where R6 is hydrogen or lower alkyl. Formula I-A2 represents this embodiment as a compound of formula I-A. Formula I-B2 represents this embodiment as a compound of formula I-B.
In most tetrazoles of this invention, it is preferred that R1 be 
It is also preferred that R5 be lower alkyl (such as methyl). It is further preferred that R3 be cyclopentyl, although cyclohexyl and cycloheptyl are also possible. When R4 is a six-membered heteroaromatic ring, it is preferably substituted or unsubstituted pyridine. When R4 is a 5-membered heteroaromatic ring, it is preferably substituted or unsubstituted thiazole. When substituted, either ring is preferably monosubstituted, and the preferred substituent is halogen such as bromo. R2 is preferably halogen (such as fluoro or chloro) or perfluoro lower alkyl (such as trifluoromethyl) and R6 is preferably methyl. Thus, a tetrazole of formula IA or IB may include any one or more of these conditions in any selected combination. In addition, any one or more of these conditions may be applied to any tetrazole of this invention as described herein. For example, in any tetrazole of this invention with substituted pyridine, the preferred substituent is bromo.
In particular, in tetrazoles of formula I-A1, R1 is 
R5 is lower alkyl, and R3 is cyclopentyl (formula I-A1a). In one embodiment of formula I-A1a, R4 is a six-membered heteroaromatic ring, in particular substituted or unsubstituted pyridine. In such a tetrazole, R2 may be halogen. An example is:
(E)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylamide
In another embodiment of formula I-A1a, R4 is a 5-membered heteroaromatic ring, in particular substituted or unsubstituted thiazole. In such a tetrazole, R2 may be halogen or perfluoro lower alkyl, or R2 may be lower alkyl sulfonyl. Examples of the former tetrazoles are
(E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl-]-N-thiazol-2-yl-acrylamide
(E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl-]-but-2-enoic acid-thiazol-2-ylamide
(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide
(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide
An example of the latter tetrazole is
(E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl-]-N-thiazol-2-yl-acrylamide
In another tetrazole of formula I-A1, R1 is 
R2 is halogen and R4 is substituted or unsubstituted thiazole. In these tetrazoles, R5 is lower alkyl or perfluoro lower alkyl. R3 may be cyclohexyl, as in
(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide
(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide
Or R3 may be cycloheptyl, as in
(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide
(E)-N-(5-bromo-thiazol-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylamide
This invention is also directed to tetrazoles of formula I-A2 (i.e. tetrazoles of formula I-A) where R4 is xe2x80x94C(O)xe2x80x94NHR6 where R6 is hydrogen or lower alkyl. In preferred such tetrazoles, R1 is 
R5 is lower alkyl, R3 is cyclopentyl, and R6 is methyl, especially where R2 is halogen. An example of such a tetrazole is
(E)-1-{3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl-acryloyl}3-methyl-urea
This invention is also directed to tetrazoles of formula I-B, for example tetrazoles of formula I-B1 (where R4 is a five- or six-membered heteroaromatic ring as described in detail above). In such tetrazoles, R4 is preferably 
R5 is lower alkyl, and R3 is cyclopentyl (formula I-B1a). In one embodiment of formula I-B1a, R4 is a six-membered heteroaromatic ring, in particular substituted or unsubstituted pyridine. In such a tetrazole, R2 may be halogen. Examples of such tetrazoles are
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide
Alternatively, R2 may be perfluoro lower alkyl, for example in
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionamide
In another embodiment of formula I-B1a, R4 is a 5-membered heteroaromatic ring, in particular substituted or unsubstituted thiazole. In such a tetrazole, R2 may be halogen or perfluoro lower alkyl, or R2 may be lower alkyl sulfonyl. Examples of these tetrazoles are
3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide
2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide
3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-propionamide
In another tetrazole of formula I-B1, R1 is 
R3 is cyclohexyl and R4 is substituted or unsubstituted thiazole. In these tetrazoles, R2 is halogen. R5 may be lower alkyl as in 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide or perfluoro lower alkyl as in 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide.
In any tetrazoles of this invention, R2 and R1 can be exchanged so that R2 is 
in particular certain tetrazoles of formula I-B1. In these tetrazoles, it is preferred that R1 is lower alkyl sulfonyl, R4 is substituted or unsubstituted thiazole, and R3 is cyclopentyl. An example of such a tetrazole is
3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide
This invention is also directed to tetrazoles of formula I-B2 (i.e. tetrazoles of formula I-B) where R4 is xe2x80x94C(O)xe2x80x94NHR6 where R6 is hydrogen or lower alkyl. In such tetrazoles, it is preferred that R1 is 
R3 is cyclopentyl, R6 is methyl, and R2 is perfluoro lower alkyl or halogen. Examples of such tetrazoles are
1-{3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl}-propionyl-3-methyl-urea
1-{2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionyl-3-methyl-urea
As used herein, the term xe2x80x9clower alkylxe2x80x9d means straight chain or branched chain alkyl groups having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl. As used herein, xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring having from 3 to 8 carbon atoms, preferably from 5 to 7 carbon atoms. As used herein, xe2x80x9cperfluoro-lower alkylxe2x80x9d means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro, such as trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc.
As used herein, xe2x80x9clower alkyl sulfonylxe2x80x9d means a lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in the sulfonyl group.
As used herein, the term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d unless otherwise stated designates all four halogens, i.e. fluorine, chlorine, bromine and iodine (fluoro, chloro, bromo, and iodo).
The heteroaromatic ring defined by R4 is five- or six-membered heteroaromatic ring (e.g. an aromatic ring having at least one heteroatom) which is connected by a ring carbon to the amide group shown in formula IA or formula IB. This ring has from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The nitrogen is found adjacent to the connecting ring carbon atom. Preferred heteroaromatic rings include pyridinyl and thiazolyl. The rings may be unsubstituted, or mono-substituted with a halogen at a position on a ring carbon which is not adjacent to the connecting ring carbon atom.
The term xe2x80x9ctransxe2x80x9d as used herein designates that the largest substituents attached across the double bond are on opposite sides of the double bond and have the xe2x80x9cExe2x80x9d configuration. The term xe2x80x9ccisxe2x80x9d designates that the two largest substituents attached across the double bond are on the same side as the double bond.
In the compounds of formula I-B, the xe2x80x9c*xe2x80x9d designates the asymmetric carbon atom in the compounds with the R optical configuration being preferred. The compounds of formula I-B may be present in the R form or as a racemic or other mixture of compounds having the R and S optical configuration at the asymmetric carbon shown. The pure R enantiomers are preferred. As stated above, the compounds of this invention are useful as glucokinase activators for increasing insulin secretion for treatment of type II diabetes. Compounds of formula I-A having the trans configuration across the double bond (represented by the xcex94) have this glucokinase activity.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid and the like. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques.
The three Schemes that follow demonstrate how to make tetrazoles of formulae IA or IB from known starting materials. 
R1, R2, R3, R4, R5, and n are as in formulae I-A and I-B. As shown in the Schemes, the R1 and R2 positions are interchangeable. Therefore the Schemes include and demonstrate the same reactions, intermediates, and compounds with the tetrazole or its precursors in the R2 position and the other R1/R2 variables (hydrogen, halogen, lower alkyl sulfonyl, perfluoro lower alkyl, cyano, or nitro) in the R1 position and vice versa.
The compounds of this invention are produced by reacting phenyl-substituted tetrazoles (II, IIxe2x80x2, IV, or IVxe2x80x2) with cycloalkyl-substituted acrylic acid lower alkyl esters (VII) to obtain tetrazolyl-phenyl cycloalkyl propenoic ester (VIII), which is hydrolyzed or reduced and hydrolyzed to give the corresponding propenoic or acrylic acid (IX or XIII), to which is added the desired heteroaromatic ring or urea/substituted urea to obtain a compound of formula I-A or formula I-B. The phenyl-substituted tetrazoles (II, IIxe2x80x2, IV, or IVxe2x80x2) may be produced from the appropriate substituted anilines which are known and available materials or can be produced by a skilled person from known materials. The cycloalkyl-substituted acrylic acid lower alkyl esters may be produced from cycloalkyl halides, which are similarly known and available materials or can be produced by a skilled person from known materials. These reactions are discussed in more detail below.
Scheme 1 shows how to obtain starting materials for compounds of this invention. For compounds where R5 is lower alkyl or perfluoro lower alkyl, substituted aniline I is reacted with lower alkyl or perfluoro lower alkyl carboxylic acid (corresponding to R5) using conventional methods for converting an amine to an imine, for example in a suspension of triphenylphosphine in carbon tetrachloride treated with an organic base such as triethylamine. Accordingly the reaction proceeds by way of an imidoyl halide (e.g. chloride) intermediate, which is reacted with an azide such as sodium azide as to obtain tetrazole II by conventional methods for tetrazole formation from an imidoyl chloride.
For compounds of this invention where R5 is lower alkyl, an alternate route is acylation of aniline I as described above to acetamide III under standard conditions (such as acetic anhydride in tetrahydrofuran), followed by reaction with an azide to obtain tetrazole IV by conventional methods for tetrazole formation from a lower alkyl amide.
Aniline I where X is either iodo or bromo and either of R1 or R2 is hydrogen, nitro, fluorine, chlorine, bromine, thiol, and trifluoromethyl or where R1 is thiomethyl or where R2 is cyano, is known and commercially available, and may also be made by a skilled chemist from known materials. Other aniline I compounds may be made by a skilled chemist from known materials.
For example aniline 1 where R1 or R2 is C1-C4 lower alkyl sulfonyl can be made from aniline I where R1 or R2 is thiol. The thiol is alkylated under standard conditions to provide the lower alkyl thio, which can then be oxidized to the corresponding lower alkyl sulfonyl. Any conventional method of oxidizing alkyl thio substituents to sulfones can be used to effect this conversion.
Aniline I where R1 is cyano (and X is bromo) can be made from aniline I where R1 is nitro and X is bromo by reducing the nitro to an amine by any conventional method, then diazotizing the amine to the corresponding diazonium salt, and reacting with a standard cyano group transferring agent to obtain aniline I where R1 is cyano.
Aniline I where R1 or R2 are perfluoro lower alkyl can be made from the corresponding halo compounds of formula VIII. Any conventional method for converting an aromatic halo group to a desired perfluoro lower alkyl group may be used (see for example, Katayama, T.; Umeno, M., Chem. Lett. 1991, 2073; Reddy, G. S.; Tam., Organometallics, 1984, 3, 630; Novak, J.; Salemink, C. A., Synthesis, 1983, 7, 597; Eapen, K. C.; Dua, S. S.; Tamboroski, C., J. Org. Chem. 1984, 49, 478; Chen, Q, -Y.; Duan, J. -X. J. Chem. Soc. Chem. Comm. 1993, 1389; Clark, J. H.; McClinton, M. A.; Jone, C. W.; Landon, P.; Bisohp, D.; Blade, R. J., Tetrahedron Lett. 1989, 2133; Powell, R. L.; Heaton, C. A, U.S. Pat. No. 5,113,013).
Aniline I where R1 or R2 is iodo may be made from the corresponding nitro compounds of formula VIII. The nitro is reduced to an amine and the amine is diazotized to the diazonium salt, which is then converted to the iodo compound by conventional methods (see for example Lucas, H. J. and Kennedy, E. R., Org. Synth. Coll. Vol. II 1943, 351).
For compounds of formula I-A, the above tetrazoles are coupled with acrylic acid lower alkyl ester (VIII) to ultimately provide tetrazolyl-phenyl cycloalkyl propenoic acid IX to which may be coupled a heteroaromatic amine or a urea or lower alkyl urea to obtain a compound of formula I-A.
Scheme 2 shows how to obtain compounds of formula I-A in more detail. R3 is cycloalkyl. To obtain cycloalkyl-2-iodo-acrylic acid methyl ester VII, organozinc reagent Va (obtained by conventional methods from commercially available iodide V) or commercially available Grignard reagent Vb and soluble copper reagent is reacted with lower alkyl propiolate in a regio- and stereo-selective 1,4-conjugate addition to obtain a vinylcopper intermediate which upon iodonolysis under standard conditions produces VII where R3 and the iodo substituent are in syn relationship to each other. The addition operates by way of a cycloalkyl copper cyano zinc or magnesium halide intermediate obtained by treating Va or Vb with copper cyanide and lithium chloride in an aprotic solvent such as tetrahydrofuran. Compound VII is then reacted with activated zinc metal (Knochel and Rao, Tetrahedron 49:29, 1993) to give a vinylzinc intermediate which may be coupled with either compound II or compound IV in the presence of a source of Pd(0) to give tetrazole-phenyl-cycloalkyl-acrylic acid methyl ester VIII with the phenyl-substituted tetrazole replacing the iodide to yield the trans orientation across the double bond.
Compound VIII is then hydrolyzed under standard alkaline conditions to the corresponding acid IX. Heterocyclic compound X may then be formed by coupling the desired heteroaromatic amine to compound IX under conventional conditions for adding an amine to an acid. Urea compound XI may be obtained by coupling urea or lower alkyl urea to compound IX under conventional conditions for converting an acid to a urea.
Compound VIII is the starting material for compounds of formula I-B. As shown in Scheme 3, these compounds may be obtained by reducing compound VIII to tetrazole-phenyl-cycloalkyl propanoic acid lower alkyl ester XII. This can be accomplished using conventional metal catalysts such as nickel in the presence of a reducing agent under standard conditions. Compound XII is then hydrolyzed under standard conditions to provide the corresponding acid XIII. Heterocyclic compound XIV may then be formed by coupling the desired heteroaromatic amine to compound XIII under conventional conditions for adding an amine to an acid. Urea compound XV may be obtained by coupling urea or lower alkyl urea to compound XIII under conventional conditions for converting an acid to a urea.
If it is desired to produce the R enantiomer of the compound of formula I-B free of the other enantiomers, the compound of formula XIII can be separated into this isomer from its racemate by any conventional chemical means. Among the preferred chemical means is to react the compound of formula XIII with an optically active base. Any conventional optically active base can be utilized to carry out this resolution. Among the preferred optically active bases are the optically active amine bases such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha-methylnaphthylamine. Any of the conventional techniques utilized in resolving organic acids with optically active organic amine bases can be utilized in carrying out this reaction.
In the resolution step, the compound of formula XIII is reacted with the optically active base in an inert organic solvent medium to produce salts of the optically active amine with both the R and S isomers of the compound of formula XIII. In the formation of these salts, temperatures and pressure are not critical and the salt formation can take place at room temperature and atmospheric pressure. The R and S salts can be separated by any conventional method such as fractional crystallization. After crystallization, each of the salts can be converted to the respective compounds of formula XIII in the R and S configuration by hydrolysis with an acid. Among the preferred acids are dilute aqueous acids, i.e., from about 0.001N to 2N aqueous acids, such as aqueous sulfuric or aqueous hydrochloric acid. By means of measuring the optical rotation of the optically pure crystallized acid of formula XIII, one can obtain the configuration of this crystalline material. If this crystallized acid has a negative rotation, then this crystallized acid has the R configuration. The configuration of formula XIII which is produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R of formula IB. The separation of R and S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl esters corresponding to the compound of the formula XII (see, for example, Ahmar, M.; Girard, C.; Bloch, R., Tetrahedron Lett, 1989, 7053), which results in the formation of corresponding chiral acid and chiral ester. The ester and the acid can be separated by any conventional method of separating an acid from an ester. The preferred method of resolution of racemates of the compounds of the formula XIII is via the formation of corresponding diastereomeric esters or amides. These diastereomeric esters or amides can be prepared by coupling the carboxylic acids of the formula XIII with a chiral alcohol or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine. The corresponding diastereomers of compounds of the formula XIII can then be separated using any conventional separation methods. The resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the corresponding pure R and S isomers. The hydrolysis reaction can be carried out using any conventional method to hydrolyze an ester or an amide without racemization.
All of the compounds of formula IA or formula IB described in the Examples activated glucokinase in vitro in accordance with the procedure described in Example A.
The following compounds were tested and found to have excellent glucokinase activating activity in vivo when administered orally in accordance with the procedure described in Example B.
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionamide
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionamide
3-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-propionamide
(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide
(E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide
(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide
(E)-N-(5-bromo-thiazol-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylamide
(E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-acrylamide
(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide